REVIEW Open Access Bicarbonate in diabetic ketoacidosis - a systematic review Horng Ruey Chua 1 , Antoine Schneider 1 and Rinaldo Bellomo 1,2* Abstract Objective: This study was designed to examine the efficacy and risk of bicarbonate administration in the emergent treatment of severe acidemia in diabetic ketoacidosis (DKA). Methods: PUBMED database was used to identify potentially relevant articles in the pediatric and adult DKA populations. DKA intervention studies on bicarbonate administration versus no bicarbonate in the emergent therapy, acid-base studies, studies on risk association with cerebral edema, and related case reports, were selected for review. Two reviewers independently conducted data extraction and assessed the citation relevance for inclusion. Results: From 508 potentially relevant articles, 44 were included in the systematic review, including three adult randomized controlled trials (RCT) on bicarbonate administration versus no bicarbonate in DKA. We observed a marked heterogeneity in pH threshold, concentration, amount, and timing for bicarbonate administration in various studies. Two RCTs demonstrated transient improvement in metabolic acidosis with bicarbonate treatmen t within the initial 2 hours. There was no evidence of improved glycemic control or clinical efficacy. There was retrospective evidence of increased risk for cerebral edema and prolonged hospitalization in children who received bicarbonate, and weak evidence of transient paradoxical worsening of ketosis, and increased need for potassium supplementation. No studies involved patients with an initial pH < 6.85. Conclusions: The evidence to date does not justify the administration of bicarbonate for the emergent treatment of DKA, especially in the pediatric population, in view of possible clinical harm and lack of sustained benefits. Introduction Diabetic ketoacidosis (DKA) is a serious medical emer- gency resulting from relative or absolute insulin defi- ciency and the unopposed action of counter-regulatory hormones, such as glucagon, cortisol, and catechola- mines [1]. The hepatic met abolism of free fatty acids generates ketoanions, such as beta-hydroxybutyrate and acetoacetate [2,3]. Impaired tissue perfusion due to volume contraction and the a drenergic response to the often severe underlying precipitating illness result in lac- tate production [4]. Acut e kidney injury leads to accu- mulation of other unmeasured anions, such as sulphate, urate, and phosphate [5]. All these, together with hyper- chloremia which pre dominates during the recovery phase of DKA [6], contribute to the development of acidemia, which often is severe [7,8]. Experimental studies suggest that metabolic acidemia can i mpair myocardial contractility, r educe cardiac out- put, affect oxyhemoglobin dissociation and tissue oxygen delivery, inhibit intracellular enzymes, such as phospho- fructokinase, alter cellular metabolism, and result in vital organ dysfunction [9-12]. Thus, the target of ther- apy in DKA has historically placed importance on the rapid reversal o f acidemia, in addition to the correction of dehydration and insulin deficiency. As a result of the physiological paradigm, correction of severe acute acidemia with intravenous bicarbonate to attenuate the deleterious effects continues to be uti- lized by some practitioners. This approach has received wide acceptance in the past, but based on currently available evidence, and concerns about the potential adverse effects in children and adults, the administration of bicarbonate in DKA requires re-examination. The objective of this systemic review was to examine the medical evidence to date, on the administration of * Correspondence: Rinaldo.BELLOMO@austin.org.au 1 Department of Intensive Care, Austin Health, Melbourne, Victoria, Australia Full list of author information is available at the end of the article Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 © 2011 Chua et al; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) , which permits unrestricted use, distribution, and reproduction in any medium, provided the or iginal work is properly cited . bicarbonate versus no bicarbonate, in the emergent treatment of severe acidemia in pediatric and adult patients with DKA, with regards to the physiological and clinical efficacies and harms of this intervention. Methods Information source Literature search was performed using the PUBMED database. The list of potentially relevant article titles and abstracts was generated by using the keywords, “bicarbo- nate” AND “diabetic ketoacidosis.” Study selection and eligibility criteria Two investigators (HC and AS) independently reviewed the article titles and abstracts. The following exclusion criteria were first applied: 1) review articles; 2) commen- taries, letters, or editorials; 3) non-English articles; 4) animal studies; 5) all articles not related to acid-base issues, bicarbonate use, or cerebral edema in DKA; 6) publications before 1960. The remaining papers were deemed relevant if they fulfilled the following inclusion criteria: 1. Population: Both adult and pediatric populations with diagnosis of DKA 2. Intervention: Intravenous sodium bicarbonate therapy 3. Comparator: Bicarbonate administration versus no bicarbonat e for the emergent tre atment of diabetic ketoacidosis 4.Outcome:Primaryoutcomesarethedifferencein mortality and duration of hospitalization. Secondary out- come is a combination of various physiological and clin- ical outcomes. Physiological outcomes include reso lution of acidosis and ketosis, insulin sensitivity and glycemic control, potassium balance, tissue oxygenation, and cerebrospinal fluid (CSF) acidosis. Clinical outcomes include hemodynamic stability and neurological out- comes, including that of cerebral edema (CE) 5. Study type: All trials, including randomized and nonrandomized case-control studies, as well as case reports and series were selected. Two investigators (HC and AS) reviewed all remaining papers in entirety after the application of the above- mentioned criteria. A third independent investigator (RB) adjudicated any disagreements regarding paper inclusion. Results Search results The systematic search identified 508 potentially relevant citations. Following application of the inclusion and exclusion criteria, 44 articles were eventually selected and the full manuscripts were reviewed. The selection process is illustrated in Figure 1. Study characteristics Twelve publications were case-controlled studies on bicarbonate administration versus no bicarbonate in DKA. Of these, two studies were nonblinded rando- mized controlled trials (RCT) [13,14], and one study was a double-b lind RCT [15]. A total of 73 adult patients were included in these three RCTs. The remaining nine studies were nonrandomized, prospec- tive, or retrospective studies, which include six adult studies [16-21], two involving both adult and pediatric patients [22,23], and one pediatric study [24]. No RCTs have been performed in the pediatric cohort, and no trials have examined bicarbonate treatment in DKA patients with an admission pH < 6.85. In addition, four pediatric nonrandomized prospective and retrospective studies investigated the association between bicarbonate administration in DKA and risk of CE [25-28]. There were no similar studies in the adult DKA cohort. Study threshold for and dose of bicarbonate In Table 1 we summarized the threshold for bicarbonate administration in various studies, which includes the initial degree of acidemia and base deficit [4,13-24,29-36]. There is heterogeneity of initial pH threshold for bicarbonate therapy, which has become more stringent over the years, from pH < 7.20 in the past to pH < 7.00. Dosing methods vary widely with study design and physician preference, andthesearesummarizedin Table 2. Concentrated bicarbonate dosing based on cal- culations using predictive formulas incorporating base deficit [37,38] results in a tendency for over- correc tion and alkalosis [29,30]. Aiming for a more modest and intermediate pH target with bicarbonate dose less than half of that predicted, or dose titrated based on pH severity, were some of the variable approaches adopted subsequently by investigators [4,23]. Consequentially, the average bica rbonate dose reported in studies appears to have decreased over the years to an overall a mount of 120-150 mmol for adults and 2 mmol/kg for children. Slow infusions using half-isotonic or isotonic prepara- tions (approximately 1%) or small intermittent boluses of more concentrated preparation s (approximately 8.4%) were preferenti ally used in later studies [13-15 ,17,1 8,20] toavoidtoorapidpHorosmolalitychanges,withno evidence of risk or benefit with either methods. Primary outcomes Duration of hospitalization One single-center retrospective pediatric study assessed duration of hospitalization as an outc ome measure [24]. Duration of hospitalization was significantly longer (87 vs. 67 hours, p = 0.01) for the bicarbonate group vs. children treated without bicarbonate. However, there Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 2 of 12 was no adjustment for confounding variables. With mul- tivariate analysis, duration o f hospitalization was 23% longer in the bicarbonate group but did not reach statis- tical significance (p = 0.07). Using 29 pairs of matched patients (for calendar year, pH, and creatinine), duration of hospitalization was 37% longer in the bicarbonate group (p = 0.011). In another brief report of 41 patients admitted for severe DKA, 5 patients h ad pH < 7.0 (mean 6.85 ± 0.09); only 4 received a small 50- mmol bolus of sodi um 508 articles retrieved from PUBMED, using the search terms: “Bicarbonate” AND “Diabetic ketoacidosis”  464 articles as listed below were excluded: - 94 review articles - 29 commentaries/letters/editorials - 80 non-English articles - 15 animal studies - 159 DKA articles not related to acid- base issues, bicarbonate use, or cerebral edema - 87 articles not related to DKA 44 articles reviewed in entirety, including: - 14 case reports/series on use of bicarbonate in DKA - 8 acid-base studies in DKA - 12 case-control studies on use of bicarbonate in DKA, including 3 RCT - 6 case reports of cerebral edema in DKA - 4 studies on risk of cerebral edema in DKA Figure 1 Overview of study selection process. Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 3 of 12 bicarbonate, whereas 36 patients with pH > 7.0 (mean 7.15 ± 0.11) did not [21]. Bicarbonate therapy did not seem to have an impact on duration of hospitalization. Therefore, there m ay be a weak association with pro- longed hospitalization in children with DKA treated with additional bicarbonat e therapy, but the evidence is of very poor quality. Mortality outcome No published trials on the use of bicarbonate therapy in DKA were able to comment on any mort ality difference with or without its use. Critically ill DKA cases with severe metabolic acidemia were excluded from most studies. Secondary outcomes (physiological) Resolution of acidosis Eight case-control studies have examined the rates of acidosis reversal with or without additional bicarbonate therapy, including three RCTs. The results are summar- ized in Table 3. Improvements in pH and serum bicar- bonate levels were used as markers of acidosis reversal [13-15,17-20,24]. Two adult RCTs demonstrated biochemical benefit in terms of acidosis reversal time, with improved pH and bicarbonate levels at 2 hours of therapy in the bicarbo- nate arm. Of these, one study administered isotonic bicarbonate as a slow infusion [13], whereas the other administered small intermittent bicarbonate boluse s of higher concentration titrated to sev erity of pH [15]. The latter study extended the follow-up duration to 24 hours of therapy and did not find a sustained biochemical ben- efit beyond 2 hours. A third adult RCT administered similar incremental small boluses of sodium bicarbonate but did not establish a similar biochemical advantage [14]. In addition, three retrospective adult studies [17,18,20] and one retrospective pediatric study [24] showed no improv ement in acidosis resolutio n with use of bicarbonate therapy. Resolution of ketosis As shown in Table 3 two adult studies showed paradox- ical worsening of ketonemia, including a slower decline in ketonemia in the first hour of bicarbonate infusion in a RCT [13], and an increase in plasma acetoacetate levels during the initial three hours of bicarbo nate infu- sion in a small, prospective, nonrandomized study [19]. Insulin sensitivity and glycemic control Results of pediatric and adult studies that reported insu- lin sensitivity and glycemic control as outcome measures Table 1 Degree of baseline acidemia and base deficit in DKA patients with bicarbonate administered Reference Population Nature of study Mean initial blood indices pH Base deficit Bicarb (mmol/L) Addis 1964 [29] A. (N = 3) Case series 6.94 Mostly unavailable Kuzemko 1969 [30] P. (N = 6) Case series 7.05 23 8.0 Zimmet 1970 [4] A. (N = 11) Case series 7.09 24 4.4 Soler 1972 [22] A+P. (N = 18) Prospective C-C < 7.2 NR < 10.0 Krumlik 1973 [31] P. (N = 27) Case series 7.05 NR 7.6 Soler 1974 [32] A. (N = 1) Case report 6.85 NR 6.0 Munk 1974 [16] P. (N = 5) Prospective C-C 7.05 22 8.7 Assal 1974 [23] A+P. (N = 9) Retrospective C-C 7.06 NR 5.6 Keller 1975 [33] A. (N = 58)* Case series < 7.2 NR NR Reddy 1977 [34] P. (N = 19) Case series 7.07 NR 6.5 Lutterman 1979 [17] A. (N = 12) Retrospective C-C 6.89 NR NR Lever 1983 [18] A. (N = 52) Retrospective C-C 6.94-7.00 † NR 3.4-4.3 † Hale 1984 [13] A. (N = 16) RCT 6.85 NR 7.0 Morris 1986 [14] ‡ A. (N = 10) RCT 7.03 NR 3.6 Gamba 1991 [15] ‡ A. (N = 9) RCT (DB) 7.05 NR 2.9 Okuda 1996 [19] A. (N = 3) Prospective C-C 6.98 NR 2.0 Green 1998 [24] P. (N = 57) Retrospective C-C 7.02 40 NR Viallon 1999 [20] A. (N = 24) Retrospective C-C 6.93 NR 3.1 Latif 2002 [21] A. (N = 4) Retrospective C-C 6.85 NR NR Kamarzaman 2009 [35] A. (N = 1) Case report 6.27 41 4.0 Guneysel 2009 [36] A. (N = 1) Case report 6.82 27 8.4 A = adults; P = pediatrics; N = number of patients who received bicarbonate, if breakdown available; C-C = case-control; RCT = randomized, controlled trial; DB = double-blinded; Bicarb = bicarbonate level; NR = not reported. *Breakdown of patients with or without bicarbonate administered not provided. † Mean values provided separately for two different study centers. ‡ Patients with initial pH < 6.9 were excluded from the RCT. Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 4 of 12 are summarized in Table 4. No significant difference in rate of glucose decline or insulin requirement was demonstrated with bicarbonate treatment. Potassium balance Seven studies examined potassium balance as an out- come measure and are summarized in Table 5. One double-blind adult RCT, with mean bicarbonate dose of 84 ± 34 mmol, demonstrated lower serum potassium at 24 hours of therapy in the bicarbonate arm [15]. Another adult retrospective study, with mean bicarbo- nate dose of 120 ± 40 mmol, showed higher potassium supplementation in bicarbonate arm over 24 hours [20]. Four other studies (including one pediatric study) did not detect any statistical difference in the potassium bal- ance [14,17,18,24]. A mixed adult and pediatric, three-arm prospective study, examined the association between mean cumula- tive bicarbonate d oses and potassium requirement. The two groups that received saline and low-dose bicarbo- nate (mean 200 mmol) had comparable potassium sup- plementation during first 24 hours, whereas the third group with high bicarbonate dose (mean 400 mmol) received higher potassium supplementation [22]. Tissue oxygenation One adult RCT reported a significantly slower rate of decline i n blood lactate and lactate to pyruvate ratio in the bicarbonate treatment arm, compared with saline control, in the first hour of treatment in DKA [13]. A slow decline in blood lactate to pyruvate ratio was used to imply tissue hypoxia. A subsequent pediatric nonran- domized prospective study demonstrated that the initial decline of in vivo P 50 (partial pressure of oxygen required to saturate 50% of the hemoglobin oxygen binding sites in a sample of whole blood) with DKA treat ment was similar in both bicarbonate-treated group and controls. Bicarbonate therapy was not shown to affect oxygen transport adversely [16]. Cerebrospinal fluid acidosis One adult RCT performed CSF a nalysis in approxi- mately half of the adult patient cohort to investigate the concern of paradoxical CSF acidosis with bicarbonate administration. The study did not find any statistically significant difference in CSF pH and bicarbonate levels within 24 hours in the bicarbonate-treatment group and control. However, patient numbers were small, and a trend for larger decline in CSF pH at 6 to 8 hours was Table 2 Summary of bicarbonate dose administered in case series and studies Reference Nature of Study Dose of bicarbonate given (mean) Dose Estimation Timing (range) Conc (%) Total (mM) Wt-adj (mM/kg) Addis 1964 [29] CS 8.4 413 NR based on calculated dose 150 initial, and rest over 1.5 to 12 hr Kuzemko 1969 [30] P CS 8.4 255 NR based on calculated dose over 3 to 32 hr Zimmet 1970 [4] CS NR 185 NR based on pH severity within initial 4 hr (≈ half of calculated dose) Soler 1972 [22] AP PrC 1.0 200 - 400 † NR NR NR Krumlik 1973 [31] P CS 7.5 115 (3.3/kg) to reach pH ≥ 7.2 based on calculated dose half over 30 min, 144 (3.9/kg) to reach pH ≥ 7.3 rest over 2 hrs Munk 1974 [16] P PrC NR 130 2.44 NR NR Assal 1974 [23] AP ReC NR 230 NR half of calculated dose given within initial 4 hr Keller 1975 [33] CS NR 345 NR based on calculated dose within initial 24 hr Reddy 1977 [34] P CS ≈ 0.6 NR 2.50 slow infusion till pH > 7.2 over mean of 4.9 hr Lutterman 1979 [17] ReC 1.4 167 NR standard dose for all within initial 6 hr Lever 1983 [18] ReC NR 130-135 ╫ NR NR majority slow infusion Hale 1984 [13] RCT 1.3 150 NR standard dose for all over 1 hr Morris 1986 [14] RCT NR 120 NR titrated to pH, repeated till intermittent dose, over pH > 7.15 30 min; 2 hr interval Gamba 1991 [15] RCT (DB) ≈ 7.5 84 NR titrated to pH, repeated till intermittent dose, over pH rise > 0.05 30 min; 2 hr interval Okuda 1996 [19] PrC NR 200 NR standard dose (50 mmol/hr) over 4 hr Green 1998 [24] P ReC NR NR 2.08 NR NR Viallon 1999 [20] ReC 1.4 120 NR as per attending physician over 1 hr Latif 2002 [21] ReC NR 50 NR standard dose for all NR CS = case series; PrC = prospective case-control; ReC = retrospective case-control; RCT = randomized controlled trial; DB = double-blind; Conc = concentration; NR = not reported; mM = mmol; Wt-adj = weight-adjusted † Mean values provided separately for two study arms; ╫ mean values provided separately for two study centers P Pediatric studies; AP mainly adults but including pediatric patients Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 5 of 12 Table 3 Key studies on resolution of acidosis and ketosis with bicarbonate therapy in DKA References Trial design No. of patients (bicarb vs. control) Mean age (yr) and initial pH Bicarbonate infusion Control Acidosis and ketosis Hale et al. [13] RCT 16 vs. 16 47 vs. 41 (1 st hr: 1 L isotonic saline for all) Higher pH and bicarb levels at 2 hr Br Med J 1984 (single center) 6.85 vs. 6.85 2 nd hr: 1 L isotonic bicarb vs. 1L isotonic saline in bicarb arm vs. control, p < 0.01 BUT (3 rd hr: 1 L isotonic saline for all) Slower decline in blood ketone in 1st hr in bicarb arm Morris et al. [14] RCT 10 vs.11 34 vs. 28 133.8 mmol if pH 6.9- 6.99 no alkali No difference in rate of change of pH, bicarb, ketones Ann Intern Med 1986 (single center) OR 89.2 mmol if pH 7.0-7.09 OR time to reach pH 7.3 7.03 vs. 7.00 OR 44.6 mmol if pH 7.1-7.14 OR bicarb levels to reach 15 mmol/L (over 30 min, 2 hourly until pH ≥ 7.15) Gamba et al. [15] RCT 9 vs. 11 29 vs. 28 133.5 mmol/150 ml (pH 6.9-6.99) 0.9% saline, also Higher pH at 2 hr in bicarb arm, p < 0.02 Rev Inves Clin 1991 double-blind 89 mmol/100 ml (pH 7.0-7.09) in similar aliquots AND higher bicarb in bicarb arm, p < 0.01 (single center) 7.05 vs. 7.04 44.8 mmol/50 ml (pH 7.1-7.14) (over 30 min, repeated at 2 hr Change in pH and bicarb larger in bicarb arm at 2 hr, if pH increase by < 0.05) p < 0.01 Okuda et al. [19] Prospective 3 vs. 4 24 vs. 34 50 mmol/hr over 4 hr No alkali Paradoxical increase in plasma acetoacetate in 1 st 3hr J Clin Endocrinol Metab 1996 nonrandomized in bicarb arm vs. control nonblinded 6.98 vs. 7.27 (IV insulin 0.1 U/kg/hr + 0.9% saline) Increase in plasma 3- hydroxybutyrate level after bicarb (single center) (p < 0.05) ceased vs. steady decline throughout in control Lutterman et al. [17] Retrospective 12 vs. 12 41 vs. 34 167 mmol/L in 1 L Low-dose insulin No difference in mean pH rise in 1 st 2hr Diabetologia 1979 (single center) over 1 hr (if pH ≤ 7.0) IV 8 U/hr OR mean time to reach pH ≥ 7.30 6.89 (with high dose insulin OR rate of decline of ketosis mean 260 U in 1st 6 hrs) Lever et al. [18] Retrospective 52 (73 cases) 22.5-37.4 vs. mean 130-135 mmol No alkali No difference in mean change in bicarb level per hr Am J Med 1983 (2 centers) vs 24.5-48.0 (majority slow infusion) OR mean change in pH per hr 21 (22 cases) 6.94-7.00 vs. 6.89-7.07 Viallon et al. [20] Retrospective 24 vs. 15 45 vs. 47 mean 120 mmol (88- 166) No alkali No difference in variation of mean pH, bicarb level, AG Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 6 of 12 observed in the bicarbonate group [14]. In another non- randomized study, the study subjects who received addi- tional bicarbonate therapy for DKA [23] were compared with controls from an older study, which used the usual treatment with insulin and saline [39]. Bot h therapies induced a paradoxical drop in CSF pH after treatment for DKA, which was accompanied by a significantly higher CSF P CO2 and lesser increment in CSF bicarbo- nate level compared to blood, with no significant difference. Table 3 Key studies on resolution of acidosis and ketosis with bicarbonate therapy in DKA (Continued) Crit Care Med 1999 (single center) 1.4% over 1 hr infusion anion gap in 1st 24 hr 6.93 vs. 7.00 OR mean time to reach pH > 7.30 OR urine ketone clearance Green et al[24] Retrospective 57 (90 cases) 9.6 vs. 10.1 mean 2.08 mmol/kg (0.53- No alkali Unadjusted rate of bicarb rise faster in bicarb arm at Ann Emerg Med 1998 (single center) vs 7.37 mmol/kg) 24 hr, p = 0.033 (pediatric) 49 (57 cases) 7.02 vs. 7.06 No difference in bicarb rise at 12 and 24 hr, or time to reach bicarb of 20 mmol/L (matched pair and multivariate analysis) cases: DKA episodes; IV: intravenous; hr: hour; min: minutes; bicarb: bicarbonate. Table 4 Studies on insulin sensitivity and glycemic control Reference Trial design and size Bicarb dose (intervention) Insulin dose Glycemic control Hale et al. [13] RCT 150 mmol IM 20 U in 1st hr, No difference in glucose decline over 2 hr Br Med J 1984 Adults (N = 32) (standard) 6 U in both 2nd and 3rd hr Morris et al. [14] RCT 120.4 mmol Insulin 0.3 U/kg (IV + IM), No difference in time for glucose to reach 250 mg/dL Ann Intern M 1986 Adults (N = 21) (mean) then IM 7 U/hr No difference in total insulin required (1 hypoglycemia in control group) Gamba et al. [15] RCT 84 mmol IV insulin 5 U/hr No difference in glucose levels throughout 24 hrs Rev Cl In 1991 Adults (N = 20) (mean) No difference in total insulin required to reduce glucose to < 250 mg/dL, or till urine ketones were < 2+ Lutterman et al. [17] Retrospective 167 mmol High-dose insulin (mean No difference in glucose decline in 1st 2 hrs Diabetologia 1979 Adults (N = 24) (standard) 260 ± 60 U in 1st 6 hr) No difference in mean glucose in 1st 8 hours vs. low dose 8 U/hr (4 hypoglycemia in bicarb arm) Lever et al. [18] Retrospective 130-135 mmol IM or IV insulin No difference in glucose decline in 7 - 9 hrs Am J Med 1983 Adult (N = 73) (standard) 5-6 U/hr (for all) (2 hypoglycemia in bicarb arm) Viallon et al. [20] Retrospective 120 ± 40 mmol IV insulin for all No difference in normalization time of glycaemia Crit Care Med1999 Adult (N = 39) (mean) (dose unspecified) OR in mean quantity of insulin infused Green et al. [24] Retrospective 2.08 mmol/kg IV insulin for all No difference in insulin requirement in 24 hrs Ann Em Med 1998 Pediatrics (N = 106) (mean) (dose unspecified) Okuda et al. [19] Prospective 200 mmol IV 0.1 U/kg bolus insulin No difference in glucose decline over 7 - 8 hrs J Clin En M 1996 Adults (N = 7) (standard) and then IV 0.1 U/kg/hr IM = intramuscular; IV = intravenous; U = units; bicarb = bicarbonate; L = liter; hr = hour. Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 7 of 12 Secondary outcomes (clinical) Neurological deterioration and cerebral edema The possible association of bicarbonate therapy with the development of CE in DKA was highlighted in three non- randomized studies t hat investigated risk factors for CE in pediatric DKA patients (Table 6). Glaser et al. per- formed a multicenter, case-control study and identified 61 children with CE. Bicarbonate therapy was the only treatment variable associated with a greater risk of CE, after comparing with matched controls. The relative risk was 4.2 (95% confidenc e interval 1.5-12.1). Comparable proportions of children in t he CE group and matched control had bicarbonate infused within 2 hours before neurological deterioration; hence no bias was detected [25]. Two other smaller studies found a trend for bicar- bonate use and an association with CE, but the risk was not significant after adjusting for covariates, including baseline acidosis [26,27]. A fourth pediatric study demon- strated that impaired conscious level i n DKA was asso- ciated with younger age and lower initial pH, and CE cases had lower pH compared with matched controls with no CE, at every conscious level studied [28]. No stu- dies have examined CE risks in adult DKA population, in which CE has only been rarely reported [40-42]. Other neurological outcomes Three adult studies have examined neurological recovery as a secondary outcome. One RCT examined mental status at 0, 2, 6, 12, and 24 hours after therapy, and found no difference in both treatment arms [15]. Two other retrospective studies also found no difference in neurological status with bicarbona te therapy, in patients with varying degrees of impaired mental status at base- line [18,20]. There were no pediatric studies on neurolo- gical recovery. Hemodynamic outcome Three studies, i ncluding one RCT involving adult DKA patients with admission pH > 6.90, reported changes i n clinical parameters, such as heart rate, respiratory rate, Table 5 Studies on potassium balance and supplementation Reference Trial design and size Bicarb dose (intervention) Insulin dose Potassium balance and supplementation Morris et al. [14] RCT 120.4 mmol Insulin 0.3 U/kg (IV + IM), No difference in serum K decline Ann Intern Med 1986 Adults (N = 21) (mean) then IM 7 U/hr Gamba et al. [15] RCT 84 mmol IV insulin 5 U/hr Lower serum K at 24 hr for bicarb arm vs. control, Rev Cl In 1991 Adults (N = 20) (mean) p < 0.05 BUT trend for more K given in control Soler et al. [22] Prospective Grp 1: none Grp 1: 234 U/24 hr More K requirement over 24 hr for Grp 3 Lancet 1972 Mixed (N = 25) Grp 2: 200 mmol Grp 2: 287 U/24 hr Estimated 30 mmol/L of K needed for Grps 1 & 2, (3-arm study; age 13-84 yr) Grp 3: 400 mmol Grp 3: 288 U/24 hr & 40 mmol/L for Grp 3 only 2 groups randomized (per L of fluid infused) Lutterman et al. [17] Retrospective 167 mmol High-dose insulin (mean No difference in mean serum K Diabetologia 1979 Adults (N = 24) (standard) 260 ± 60 U in 1st 6 hr) No difference in K requirement over 12 hrs vs. low dose 8 U/hr Lever et al. [18] Retrospective 130-135 mmol IM or IV insulin No difference in K requirement Am J Med 1983 Adults (N = 73) (standard) 5-6 U/hr (for all) 6 hypokalemia (< 3.3 mmol/L) in bicarb arm, 1 in control Viallon et al. [20] Retrospective 120 ± 40 mmol IV insulin for all More K requirement over 24 hr for bicarb arm, Crit Care Med1999 Adults (N = 39) (mean) (dose unspecified) p < 0.001 1 hypokalemia (< 3 mmol/L) in bicarb arm Green et al. [24] Retrospective 2.08 mmol/kg IV insulin for all No difference in hypokalemia occurrence Ann Emerg Med 1998 Pediatrics (N = 106) (mean) (dose unspecified) Grp = group; IM = intramuscular; IV = intravenous; U = units; K = potassium; bicarb = bicarbonate; L = liter. Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 8 of 12 and mean arterial pressure as outcome measures. None reported any difference in clinical parameters with or without added use of bicarbonate [15,18,20]. Discussion Summary of evidence We conducted a systematic review of the literature, comparing additional use of bicarbonate infusion versus the usual treatment with insulin and hydration, in pedia- tric and adult patients with DKA. We have found marked heterogeneity and no clear evidence, with regards to the threshold for, concentration, amount, and timing of bicarbonate administration. In addition to such variability of treatment, there was retrospective evi- dence of clinical harm, such as increased risk for CE and prolonged hospitalization in children, and weak evidence of physiological harm, such as transient paradoxical worsening of ketosis and increased need for potassium supplementation. Theoretical benefits perceived with rapid acidemia reversal were not evident, apart from weak evidence of transie nt improvement in acidosis, with no evidence of any clinical efficacy. Physiological impact of bicarbonate therapy in DKA The primary ca use of acidemia in patients with DKA is ketoacidosis, with contribution from lactic acidosis and renal dysfunction. After metabolism of ketones during the recovery phase, bicarbonate is regenerated and aids the resolution of acidosis but is potentially affected by the development of hyperchloremia, which has been reported in more than 50% of adult and pediatric patients after 4 hours of therapy in DKA, and in more than 90% of patients by 8 to 20 hours [7,43 ]. It was observed and suggested in these studies that hyper- chloremic acidosis is likely contributed by preferential renal excretion of ketones over chloride anion and volume repletion with saline, with the most rapid rise in hyperchloremia coinciding with the period of greatest Table 6 Studies on risk of cerebral edema in pediatric DKA population References Trial design Case (children with CE) Control(s) Associated risks of CE Bicarb therapy and CE risk Glaser et al. [25] Retrospective N = 61 N = 174 (matched) Higher urea nitrogen and lower arterial P CO2 levels Bicarb therapy significantly a/w CE (matched control) NEJM 2001 case-control Mean age: 8.9 yr Mean age: 9.0 yr at presentation (matched and random controls) (23 of 61 with CE received bicarb; (multicenter) Mean pH: 7.06 Mean pH: 7.09 and vs. 43 of 174 matched controls); USA + Australia (matched for age, DM onset, pH/bicarb, glucose) smaller increase in Na+ (matched control) RR 4.2 (p = 0.008) N = 181 (random) and Mean age: 11.3 yr Younger age, newly dx DM, lower pH, higher Mean pH: 7.12 glucose & Cr at presentation (random control) Lawrence et al. [26] Prospective + N = 21 N = 42 (mostly random) Lower bicarb, higher urea, higher glucose levels Trend towards association for bicarb therapy with CE J Pediatrics 2005 Retrospective Mean age: 9.0 yr Mean age: 9.6 yr at presentation (data for bicarb therapy available in 17 CE cases, case-control Mean pH: 7.10 Mean pH: 7.20 with 34 random controls) (multicenter) (13 prospective,(matched for institution Canada 8 retrospective) and data collection duration) Edge et al. [27] Prospective N = 43 N = 169 Lower pH and/or lower bicarb levels, higher urea Unadjusted OR of bicarb Rx for CE risk of 3.7 (p < 0.05) Diabetologia 2006 case-control Mean age: 8.5 yr Mean age: 8.9 yr and potassium levels at presentation; After adjustments for matching variables and baseline (multicenter) Mean pH: 7.00 Mean pH: 7.20 more cumulative fluid volume given in 1st 4 hr, acidosis, OR reduced to 1.5 (not significant) United Kingdom (matched for age, sex, DM onset, admission month) insulin administration in 1st hr, and higher quantity of insulin given over 1st 2 hr DM = diabetes mellitus; bicarb = bicarbonate; Na+ = sodium; Cr = creatinine; CE = cerebral edema; neuro = neurological; RR = relative risk; OR = odds ratio; Rx = treatment. Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 9 of 12 saline administration [43]. Theoretically, adjunct use of bicarbonate administration maybemorebeneficialin the scenario of reduced renal b icarbonate genesis with concomitant acute kidney injury or in hyperchloremic acidosis where there is defici ency of bicarbonate relative to chloride. Although bicarbonate therapy in DKA has been shown in two RCTs to improve acidosis resolution in the initial few hours of therapy, the comparator consisted of sodium chloride infusion. Thus, the initial favorable physiologic outcome with bicarbonate therapy might represent a reduced risk of hyperchloremic acidosis. Despite so, patient numbers were small, and this transi- ent physiological benefit had not been demonstrated to persist beyond the initial 2 hours. Concerns were raised that bicarbonate therapy might interfere with tissue oxi- dation and with the cle arance or renal excretion of ketones, hence accounting for the paradoxical worsening of ketosis. Severe acidosis may inhibit the action of insulin on glucose utilization. Insulin resistance in humans has been shown to be higher at lower pH range and resis- tance to fall steeply at pH ab ove 7.2 [44]. Early and rapid correction of acidemia can theoretically increase insulin sensitivity. However, as discussed, there is no evidence of the above-postulated benefit of bicarbonate therapy. Instead, lower serum potassium and increased need for potassium supplementation had been demon- strated by mainly adult studies, including one small RCT, in the bicarbonate treatment arm. Although no fatal outcomes or arrhythmias had been reported as a result of hypokalemia, it would be prudent to pay close attention to this anticipated complication. Acute reversal of acidemia with bicarbonate also has been linked to worsening of tissue hypoxia. Acidosis induces a mild increase in P 50 and reduced hemoglobin- oxygen affinity (Bohr effect), but at the same time is associated with lower levels of 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes [45], which leads to a coun- teractive increased hemoglobin-oxygen affinity. In the initial presentation of DKA, a fine balance exists in favor of the former (Bohr effect) [16], which can theore- tically be disrupted by rapid treatment of acidemia, as 2,3-DPG levels were demonstrated to remain strikingly low for days despite improvement in acidosis [46], resulting in net increase in hemoglobin-oxygen affinity and impaired tissue oxygenation. However, this phe- nomenon is generally seen in the initial treatment phase of DKA, regardless of bicarbonate therapy. P 50 ,along with blood lactate to pyruvate ratio, are merely surro- gate markers of peripheral tissue oxygenation used in studies. Therefore, there remains to be insufficient evi- dence that additional bicarbonate administration affects tissue oxygenation adversely. Bicarbonate therapy in patients with DKA appeared to be associated with increased obtundation and profound cerebrospinal fluid (CSF) acidosis in an early study [47]. Apossibleexplanationforthisobservationmaybethe preferential movement across the blood-br ain barrier of CO 2 compared with bicarbonate during treatment of DKA, when both P CO2 and bicarb onate levels rise in the blood. It was postulated that rapid reversal of acidemia with bicarbonate might promote paradoxical CSF acido- sis and contribute to adverse neurological outcomes. However, we have not found any evidence that bicarbo- nate infusion causes increased paradoxical CSF acidosis compared with conventional DKA treatment. In essence, most of the theoretical biochemical gains and harm with bicarbonate administration were not evi- dent in actual case scenarios, and the overall physiologi- cal impact with such treatment is dismal. Clinical impact of bicarbonate therapy in DKA CE followed by coma is a devastating complication of DKA, with an incidence of 1% and mortality of 24% [25,27], and appears to be essentially exclusive to chil- dren and young adolescents [48]. The pathophysiology of CE remains unclear, and a detailed discussion on this is beyond the scope of this article. In essence, possible mechanisms include initial cerebral vasoconstriction and reduced cerebral blood flow from acidosis and hypocap- nia, cytotoxic edema, and cerebral injury, followed by cerebral hyperemia, reperfusion injury, and vasogenic edema, coupled with increased blood brain barrier per- meability, during the rehydration phase of DKA [48,49]. Several reports of sudden death following irreversible coma in children and young adults with DKA were pub- lished in the 1960s, including development of diabetes insipidus in some, with postmo rtem findings of CE and neuronal degeneration [50-52]. From our earlier discussion, it is apparent that cere- bral function in DKA is related to severity of acidosis, even when there is no occurrence of CE. There were no details on the reasons for bicarbonate administration in previously mentioned studies on CE in children with DKA, and it would be logical to assume that those who were given bicarbonate were likely to have more severe DKA or even circulatory collapse, factors which by themselves might predispose to adverse neurological outcomes. It should be noted that studies on risk factors for CE were based on historical cases, when the use of bicarbonate frequently accompanied high-dose insulin protocols, where the combination of both might have theoretically worsened the risk of CE. Apart from the risk of CE, we also have discussed the retrospective evidence that bicarbonate therapy is asso- ciated with prolonged hospita lization in the pediatric DKA cohort. Such studies were again subjected to the Chua et al. Annals of Intensive Care 2011, 1:23 http://www.annalsofintensivecare.com/content/1/1/23 Page 10 of 12 [...]... 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National University Health System (NUHS) Singapore The funds were utilized for his clinical and research training in Austin Health, Melbourne, Australia Author details 1 Department of Intensive Care, Austin Health, Melbourne, Victoria, Australia 2 Australia and New Zealand Intensive Care (ANZIC) - Research Centre, Monash University, Melbourne, Victoria, Australia Authors’ contributions RB and HRC conceived... treatment of diabetic ketoacidosis in an adult with new onset diabetes Neurocrit Care, United States 2005, 2:5 5-5 8 41 Hiller KM, Wolf SJ: Cerebral edema in an adult patient with diabetic ketoacidosis Am J Emerg Med, United States 2005, 23:39 9-4 00 42 Haringhuizen A, Tjan DH, Grool A, van Vugt R, van Zante AR: Fatal cerebral oedema in adult diabetic ketoacidosis Netherlands Journal of Medicine 2010, 68:3 5-3 7... ketoacidosis A comparative study of two methods Diabetologia 1979, 17:1 7-2 1 Lever E, Jaspan JB: Sodium bicarbonate therapy in severe diabetic ketoacidosis American Journal of Medicine 1983, 75:26 3-2 68 Okuda Y, Adrogue HJ, Field JB, Nohara H, Yamashita K: Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis Journal of Clinical Endocrinology & Metabolism 1996, 81:31 4-3 20 Viallon A, ... 344:26 4-2 69 Lawrence SE, Cummings EA, Gaboury I, Daneman D: Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis Journal of Pediatrics 2005, 146:68 8-6 92 Edge JA, Jakes RW, Roy Y, Hawkins M, Winter D, Ford-Adams ME, Murphy NP, Bergomi A, Widmer B, Dunger DB: The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children Diabetologia... clinical outcome, especially in the pediatric cohort Documentation of improved mental status from initial diabetic coma following treatment (including bicarbonate therapy) came only from pediatric and adult case reports and series [23,29,30,36] It could not be ascertained, however, if a favorable neurological outcome was attributable to the use of initial bicarbonate therapy In addition, there is no... anti-insulin serum and glucagon J Clin Invest 1975, 55:120 2-1 209 3 McGarry JD, Foster DW: Regulation of hepatic fatty acid oxidation and ketone body production Annu Rev Biochem 1980, 49:39 5-4 20 4 Zimmet PZ, Taft P, Ennis GC, Sheath J: Acid production in diabetic acidosis; a more rational approach to alkali replacement British Medical Journal 1970, 3:61 0-6 12 5 Calzavacca P, Lacari E, Bellomo R: Renal failure... cardiovascular and pulmonary function Kidney Int 1972, 1:37 5-3 89 Kono N, Kuwajima M, Tarui S: Alteration of glycolytic intermediary metabolism in erythrocytes during diabetic ketoacidosis and its recovery phase Diabetes 1981, 30:34 6-3 53 Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders First of two parts N Engl J Med 1998, 338:2 6-3 4 Kraut JA, Kurtz I: Use of base in the treatment . decline in ketonemia in the first hour of bicarbonate infusion in a RCT [13], and an increase in plasma acetoacetate levels during the initial three hours of bicarbo nate infu- sion in a small, prospective,. remains to be insufficient evi- dence that additional bicarbonate administration affects tissue oxygenation adversely. Bicarbonate therapy in patients with DKA appeared to be associated with increased. Elsevier Inc; 2010. doi:10.1186/211 0-5 82 0-1 -2 3 Cite this article as: Chua et al .: Bicarbonate in diabetic ketoacidosis - a systematic review. Annals of Intensive Care 2011 1:23. Chua et al. Annals